The term inflammation, as it is to be understood here, is generally understood as a reaction of the organism and its tissues to various harmful stimuli. Harmful stimuli are exogenic and endogenic stimuli, such as for instance tissue injuries, penetration by foreign bodies, chemical substances, bacterial toxins, allergens, immune complexes, microorganisms, pathological metabolic products and decomposition products of tumors. The classical symptoms, pain and fever, are closely related to the inflammation process.
It has been known for a long time that certain substances produced by the body, the so-called mediators, are closely related to the inflammation process. These mediators, which are of extremely great pathogenetic importance, are released from the body's cells by the harmful event (noxe). The most important and best-known mediators are considered to be histamine, 5-HT (5-hydroxytryptamine), bradykinin, the prostaglandins, the prostacyclins, the leukotrienes, thromboxanes and the only recently characterized platelet activating factor (PAF).
These and other mediators, which are not specified individually in detail, have an extremely great effect on the contraction of the smooth muscle, they lead to disorders of cardiac function and impair the integrity of the blood vessels and mucous membranes, such as, for example, those of the bronchial system. They also cause the aggregation of platelets and polymorphonuclear leukocytes with the severe effects of anaphylactic constriction of the airways, blood pressure reduction, cardiac arrhythmias, plasm exudation, tissue edema, hemoconcentration, thrombocytopenia, leukocytopenia, clumping of platelets and polymorphonuclear leukocytes in the pulmonary capillaries as well as highly severe respiratory disorders and circulatory collapse.
Owing to their broad pharmacological spectrum of action, their wide distribution in the organism, their formation by numerous physical, chemical, pathological, pathophysiological and pharmacological influences, as well as owing to their involvement in a large number of pathophysiological processes, the mediators and the influencing thereof by means of pharmaceuticals are of utmost medical significance (cf. "The Pharmacological Basis of Therapeutics, ed. Goodman and Gilman. 6th edition, 1980, Macmillan Publishing Company).
PAF appears to enjoy special importance in the pathogenesis of inflammatory and allergic processes.
PAF is a glycerophosphocholine with the chemical name 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine. This factor is released by a number of cells, such as macrophages, basophilic and neutrophilic granulocytes, and others, when activated. The release of PAF leads thereafter to the pathological conditions described above and probably to a number of other, hitherto not fully understood, pathological symptoms. PAF need not have a direct effect, rather it may develop its effect by stimulating other mediators. Recent studies have shown that PAF plays an important role in particular in causing clinical bronchial asthma and in other pathological conditions of the lungs, e.g. obstructive bronchitis.
In addition to its important role in causing bronchial asthma and in anaphylaxis, PAF is to be considered a highly potent inflammation mediator possessing the pathological effects already described above.
A large number of the mediators named above, including PAF, are released by a membrane-linked phospholipase from phospholipids of the cell membrane, forming arachidonic acid, on the one hand, and a preliminary stage of PAF, on the other.
Two groups of mediators are formed originating from arachidonic acid:
(i) by the enzyme, cyclooxygenase, the prostaglandins including prostacyclin and thromboxane, PA0 (ii) by the enzyme, lipoxygenase, the open chain hydroperoxy and hydroxy acids and, in particular, the leukotrienes. PA0 R.sup.2 =H, Cl, Br, I, methyl, hydroxy, methoxy, propoxy, iso-propoxy or ethoxy; PA0 R.sup.3 =H or .beta.-D-glykosyl; PA0 R.sup.4 =H, Cl, Br, I, methyl, hydroxy, methoxy, propoxy, iso-propoxy or ethoxy; PA0 R.sup.5 =H or hydroxy, PA0 R.sup.2 denotes H or C.sub.1-4 alkoxy; PA0 R.sup.3 denotes OH or a .beta.-D/alpha-L-glykosyl group (di-or-triglykosyl) which is substituted optionally by low molecular C.sub.1-4 aliphatic or aromatic acids, PA0 R.sup.4 denotes H or C.sub.1-3 alkyl or C.sub.1-4 alkoxy; PA0 R.sup.5 denotes H, Cl, Br or I, R.sup.5 being, when it denotes halogen, in ortho position to a OH group, PA0 i) an acetophenone of the general formula ##STR5## in which R.sup.1 denotes CH.sub.3 O or H, PA0 R.sup.2 denotes OH, PA0 R.sup.3 denotes H, OH or CH.sub.3 O, PA0 ii) the reaction mixture is neutralised, the precipitate formed is separated and recrystallized; PA0 iii) the product obtained in ii) is reacted in an alcoholic solution with an alcoholate; and PA0 iv) the reaction mixture is neutralisied, the solvent is removed and the residue from H.sub.2 O is recrystallized, or for the production of a halogenated acetophenone PA0 a) an acetophenone of the above general formula is dissolved in a water/methanol mixture, PA0 b) Na acetate is added and is reacted with a solution of Na-hypochlorite or K-iodide and iod (gaseous) or K-bromide and brom (gaseous) for 1.5 to 3 hours at -60.degree. C. to 90.degree. C., PA0 c) the reaction product is extracted with chloroform, is washed with Na-thiosulfate and is recrystallized from acetic acid, and it then used for preparing the final compound as mentioned above.
The preliminary stage of PAF is transferred into the active compound by an acetyltransferase.
Two groups of active substances are pharmacologically important in the treatment of inflammation; these are, on the one hand, the so-called nonsteroidal antiphlogistic agents, that is compounds and derivatives of salicylic acid. Other compounds with a well-known antiphlogistic action are the pyrazolone derivatives, the para-aminophenol derivatives, the indole derivatives (e.g. indomethacin) and the derivatives of propionic acid. The pharmacological action of all these compounds is based on the fact that they can inhibit cyclooxygenase and thus prevent the synthesis of prostaglandins or thromboxanes.
Salicylic acid and its derivatives and the further compounds of the whole class are burdened by a number of severe and highly severe side effects. Prolonged administration of salicylic acid derivatives, for instance, leads to gastric and intestinal ulcers. The relative intolerance of the pyrazolone derivatives, the hepatotoxic effect of the para-aminophenol derivatives, the general intolerance of indomethacin and the ulcerative effect of the propionic acid derivatives are also well-known.
A further severe disadvantage of nonsteroidal antiphlogistic agents is that they enhance, under certain circumstances, the pathological effect of the mediators, as the inhibition of the cyclooxygenase provides more substrate for lipoxygenase and thus for the formation of leukotrienes.
The nonsteroidal antiphlogistic agents are contrasted by the steroidal antiphlogistic agents, that is the corticosteroids and their derivatives. The antiphlogistic action of the corticosteroids is based on their ability to inhibit both phospholipase and lipoxygenase, thus inhibiting the entire arachidonic acid metabolism. The unfortunate side effects are a disadvantage for therapy with corticosteroids, and only the following are to be mentioned as examples: duodenal or ventricular ulcers, myopathy, osteoporosis, mental disorders, increased susceptibilty to infection, subcapsular cataracts and similar.
In addition to the corticosteroids, selective lipoxygenase inhibitors such as benoxaprofen are in use. This class of substances is also burdened with severe side effects, such as fatal exfoliative dermatitis (scalded skin syndrome).